CN107224585B - A composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor - Google Patents
A composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor Download PDFInfo
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- CN107224585B CN107224585B CN201610179680.7A CN201610179680A CN107224585B CN 107224585 B CN107224585 B CN 107224585B CN 201610179680 A CN201610179680 A CN 201610179680A CN 107224585 B CN107224585 B CN 107224585B
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- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 32
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 31
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- 230000005484 gravity Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229940051518 naproxen and esomeprazole Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 125000002345 steroid group Chemical group 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a composition containing a non-steroidal anti-inflammatory drug and a proton pump inhibitor and a preparation method thereof. The weight of the medicine-containing layer is 7-30% and the weight of the isolating layer is 5-15% through screening by a prescription process, and the medicine composition has good stability and uniform content and meets the pharmacopeia standard.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a composition containing a non-steroidal anti-inflammatory drug and a proton pump inhibitor and a preparation method thereof.
Background
Osteoarthritis is the most common type of arthritis, with approximately 1.51 million people worldwide suffering from osteoarthritis. The prevalence rate of people over 75 years old in China is as high as 80%, and the disability rate of the disease is as high as 53%. This situation is more serious as china gradually enters an aging society and as the life of the population in china is prolonged.
Non-steroidal anti-inflammatory drugs (NSAIDs) refer to drugs with antipyretic, analgesic and anti-inflammatory effects rather than steroid structures, which have wide application, fast action and good analgesic effect, and are first-line drugs for treating rheumatic diseases such as osteoarthritis and rheumatoid arthritis. Ibuprofen, naproxen, diclofenac, nabumetone, indomethacin, piroxicam, etc. are commonly used clinically, however, 50% of patients are at risk of developing peptic ulcers in the population treated with NSAIDs for a long period of time. Nonsteroidal drugs may increase the risk of inflammation of the gastrointestinal tract, ulceration, severe bleeding and gastric perforation, with the potential for mortality in severe cases.
Proton Pump Inhibitors (PPI) include omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, and other drugs, which can significantly inhibit the basal gastric acid secretion of normal persons and ulcer patients and the gastric acid secretion induced by the stimulation of histamine, gastrin, and the like, and can also have a protective effect on gastric mucosa.
On 30 days 4 months 2010, mixed tablets containing extended release enteric naproxen (naproxen) and immediate release esomeprazole magnesium (esomeprazole magnesium) were approved by the FDA for the treatment of arthritis under the trade name vimova. The drug design concept is that the esomeprazole magnesium is released first in the stomach and then naproxen is dissolved in the small intestine, and the enteric coating prevents the naproxen from being released below ph 5.5. The esomeprazole magnesium quick release can protect the gastrointestinal tract, create a good drug environment for naproxen in advance, and reduce the risk of gastric ulcer caused by naproxen.
CN1116899C relates to a multiple unit tableted dosage form comprising a proton pump inhibitor and an NSAID, the tablet structure being arranged from the inside to the outside as follows: the tablet core is a proton pump inhibitor drug, an isolation layer is added, enteric coating is carried out, pellets are prepared, the outermost layer is an NSAID rapid disintegration layer, and finally the proton pump inhibitor and NSAID rapid disintegration multiple unit tablet is obtained. The NSAID of the tablet obtained by the patent is quick-release, the proton pump inhibitor is enteric-coated pellets for slow release, and the side effect of the NSAID on the gastrointestinal tract is still unavoidable.
CN101683339A discloses a pharmaceutical composition containing lansoprazole and naproxen, the preparation method of the tablet is that the lansoprazole and the naproxen are mixed and tableted, the lansoprazole and the naproxen obtained in the patent are both quick-release tablets and enter the stomach, the lansoprazole and the naproxen are released at the same time, and the naproxen still has irritation effect on the stomach.
CN102209529A relates to a method for delivering a pharmaceutical composition to a patient in need thereof, wherein example 1 discloses that the PN 400 formulation is a multilayer tablet with a core of naproxen surrounded by an enteric coating and esomeprazole, but without reference to a separating layer, the enteric material is an acidic substance and esomeprazole is acid labile.
CN104208039A discloses a naproxen esomeprazole magnesium enteric-coated preparation, the preparation method is that naproxen and esomeprazole magnesium are respectively prepared into enteric pellets and film coated tablets, and the influence of acidic enteric materials on the stability of esomeprazole is avoided. However, the weight of naproxen pellets in the tablets is about 14 times that of esomeprazole magnesium film coated tablets, the tablets prepared by mixing and filling the naproxen pellets in the same capsule have the problem of uneven mixing, and meanwhile, the process has higher requirements on capsule filling machines and equipment and is difficult to realize industrial production.
Therefore, there is a need to develop a new composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor, which can exert the protective effect of the proton pump inhibitor on gastric mucosa and reduce the gastrointestinal side effects of the non-steroidal anti-inflammatory drug, and can solve the problems of acid instability and uneven content of the proton pump inhibitor.
Disclosure of Invention
In order to solve the above problems, the present invention provides a novel composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor, wherein the non-steroidal anti-inflammatory drug is delayed-release, and a separation layer is added between an enteric layer and the proton pump inhibitor to prevent the proton pump inhibitor from being unstable to acid; in further prescription process screening, the applicant finds that the content uniformity of the proton pump inhibitor is related to the weight gain of the drug-containing layer, the weight gain range of the drug-containing layer is 7-30%, the content uniformity of the obtained tablet meets the pharmacopoeia requirements, the prescription is stable and reasonable, and the requirements of industrial mass production are met.
The invention aims to provide a composition containing a non-steroidal anti-inflammatory drug and a proton pump inhibitor, the composition is a multilayer tablet, and the composition sequentially comprises a tablet core, an enteric layer, an isolation layer and a drug-containing layer from inside to outside, wherein the tablet core contains the non-steroidal anti-inflammatory drug, and the drug-containing layer contains the proton pump inhibitor, and the composition is characterized in that: the weight of the medicine-containing layer is increased by 7 to 30 percent.
The invention aims to provide a composition, wherein the tablet core comprises a non-steroidal drug, a disintegrating agent, a bonding agent and a lubricating agent; the enteric layer comprises a casing material, an anti-sticking agent and a plasticizer; the isolation layer comprises an isolation component, an anti-adhesion agent and a plasticizer; the drug-containing layer comprises a proton pump inhibitor, a binder, an anti-adhesive agent and a stabilizer.
In a preferred embodiment of the invention, the disintegrant is selected from croscarmellose sodium, crospovidone or sodium carboxymethyl starch, more preferably croscarmellose sodium ND-2HS, crospovidone CL or crospovidone XL-10, further preferably croscarmellose sodium ND-2HS or crospovidone CL, and still further preferably croscarmellose sodium ND-2 HS;
the adhesive is selected from one or more of povidone, hypromellose, hydroxypropyl cellulose or sodium carboxymethyl cellulose, preferably povidone K30, hypromellose E5 or hydroxypropyl cellulose SL, more preferably povidone K30 or hypromellose E5, and further preferably povidone K30;
the lubricant is selected from magnesium stearate, aerosil, talcum powder or polyethylene glycol, preferably magnesium stearate or aerosil;
the enteric coating material is selected from Ewing, cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate, preferably Ewing L30D-55, Ewing S100 or Ewing L100, further preferably Ewing L30D-55 or Ewing S100, further preferably Ewing L30D-55;
the anti-adhesion agent is selected from talcum powder, magnesium stearate, magnesium monostearate glyceride or superfine silica powder, preferably talcum powder, magnesium stearate or superfine silica powder, and further preferably talcum powder;
the plasticizer is selected from triethyl citrate, tributyl citrate, triacetin, phthalate, polyethylene glycol 6000 or propylene glycol, preferably triethyl citrate, tributyl citrate, polyethylene glycol 6000 or propylene glycol, more preferably triethyl citrate or polyethylene glycol 6000, and even more preferably triethyl citrate;
the isolating component is selected from one or more of hypromellose, microcrystalline cellulose or lactose monohydrate, preferably hypromellose E5 or microcrystalline cellulose, and further preferably hypromellose E5;
the stabilizer is selected from magnesium oxide, magnesium carbonate, sodium bicarbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide or ammonia water, preferably magnesium oxide, sodium carbonate, sodium hydroxide or potassium hydroxide, and further preferably sodium hydroxide or potassium hydroxide;
the non-steroidal anti-inflammatory drug is selected from ibuprofen, naproxen, diclofenac, piroxicam or nabumetone, preferably naproxen or nabumetone;
the proton pump inhibitor is selected from esomeprazole magnesium, omeprazole, lansoprazole or rabeprazole, and is preferably esomeprazole magnesium or rabeprazole;
according to the preferred embodiment of the invention, the weight of the isolation layer is increased by 5% -15%, preferably 5% -12%, and further preferably 5% -7%.
According to the preferable scheme of the invention, the weight of the medicine-containing layer is increased by 7% -30%, preferably 7% -25%, and further preferably 7% -15%.
According to the preferable scheme of the invention, when the weight of the enteric layer is increased within the range of 8% -10%, the tablet does not swell and dissolve in 0.1mol/L hydrochloric acid solution for 2 hours, and the acid resistance is better.
The invention aims to provide a composition, which has the following prescription per unit specification:
tablet core
500mg of non-steroidal anti-inflammatory drug
Disintegrating agent 20-30mg
20-30mg of adhesive
Lubricant 5-10mg
Enteric layer
Casing material 35-40mg
8-14mg of antiadhesive agent
2.5-5mg of a plasticizer,
insulating layer
Isolating component 20-60mg
2-10mg of antiadhesive agent
2-6mg of plasticizer, 5-12% of weight increment of isolating layer,
medicine containing layer
Proton pump inhibitor 20mg
2-90mg of adhesive
1-60mg of antiadhesive agent
1-4mg of stabilizer, and 7-25% of weight of the medicine-containing layer.
Another object of the present invention is to provide a process for the preparation of a composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor, characterized in that it comprises the steps of:
(1) tablet core: weighing the non-steroidal drugs and the disintegrating agents according to the prescription amount, preparing soft materials by using adhesives, granulating by 20 meshes, drying, adding the lubricants according to the prescription amount, mixing and tabletting to obtain tablet cores;
(2) enteric layer: dissolving an anti-sticking agent and a plasticizer in water, adding a casing material, and uniformly stirring to obtain an enteric coating solution; adding the tablet core in the step (1) into a coating pan, starting a machine, and coating an enteric coating;
(3) isolation layer: dissolving a plasticizer in ethanol, sequentially adding an isolation component, water and an anti-sticking agent, and uniformly stirring to obtain an isolation layer coating solution; putting the tablet core coated with the enteric-coated layer in the coating pan, starting a machine, and coating an isolating layer;
(4) a medicine-containing layer: dissolving a proton pump inhibitor drug and a stabilizer in ethanol, sequentially adding an adhesive, water and an anti-sticking agent, and uniformly stirring to obtain a drug-containing layer coating solution; placing the tablet core coated with the isolating layer in the coating pan, and starting the machine to contain the medicine layer.
The present invention relates to a composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor for use in the manufacture of a medicament for the treatment of gastrointestinal side-effects associated with diseases with a non-steroidal anti-inflammatory drug.
Compared with the prior art, the invention has the beneficial effects that:
(1) the tablet layer structure comprises a tablet core, an enteric layer, an isolation layer and a drug-containing layer from inside to outside in sequence, wherein a proton pump inhibitor is released firstly, so that the side effect of the non-steroidal anti-inflammatory drug on gastrointestinal tracts is avoided;
(2) according to the invention, the isolating layer is added between the enteric-coated layer and the drug-containing layer, so that the problem that the proton pump inhibitor is sensitive to acid is solved, furthermore, the isolating layer can play a better isolating effect when the weight increment range is 5% -12%, and the prepared tablet has better stability;
(3) the composition of the non-steroidal anti-inflammatory drug and the proton pump inhibitor has small specific gravity of the proton pump inhibitor, the weight of the proton pump inhibitor is only one twenty-fifth of that of the non-steroidal anti-inflammatory drug, and the problem of uneven content of the proton pump inhibitor in a tablet is solved by controlling the weight increment range of a drug-containing layer to be 7-25%.
Interpretation of terms
Non-limiting examples of "non-steroidal anti-inflammatory drugs" include, but are not limited to, aspirin, indomethacin, sulindac, piroxicam, tolmetin, ibuprofen, acetaminophen, naproxen, flurbiprofen, diclofenac, and nabumetone;
non-limiting examples of "proton pump inhibitors" include, but are not limited to, omeprazole, lansoprazole, pantoprazole, rabeprazole, or esomeprazole, and pharmaceutically acceptable salts thereof;
non-limiting examples of "disintegrants" include, but are not limited to, corn starch, potato starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium;
non-limiting examples of "binders" include, but are not limited to, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, calcium hydroxymethyl cellulose, povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and ethyl cellulose;
non-limiting examples of "lubricants" include, but are not limited to, magnesium stearate, talc, aluminum stearate, calcium stearate, magnesium carbonate, polyethylene glycol, and glyceryl behenate;
non-limiting examples of "enteric coating materials" include, but are not limited to, ewings, cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate;
yudragit (EUDRAGIT) is a trade name for synthetic pharmaceutical excipients and includes methacrylic acid copolymers and methacrylate ester copolymers, commonly known as acrylic resins. Common Eudragit types are L30D-55, L100, S100, FS 30D, depending on the chemical composition;
ewing L30D-55 is an aqueous dispersion of a copolymer of methacrylic acid and ethyl acrylate (1:1) (polymer content 30%, i.e.30% by weight), insoluble in acidic conditions and soluble in solutions having a pH greater than 5.5;
eudragit L100-55 is Eudragit L30D-55 spray-dried product, dissolved in a solution having a pH greater than 5.5;
equidch L100 is a copolymer powder of methacrylic acid and methyl methacrylate (1:1), dissolved in a solution having a pH greater than 6;
ewing S100 is a copolymer powder of methacrylic acid and methyl methacrylate (1:2) dissolved in a solution having a pH greater than 7;
ewing FS 30D is an aqueous dispersion (polymer content 30%) of a copolymer of methacrylic acid, methyl acrylate and methyl methacrylate (1:1:1), dissolved in a solution having a pH greater than 6;
non-limiting examples of "anti-adhesive" include, but are not limited to, talc, magnesium stearate, glyceryl monostearate, and aerosil;
non-limiting examples of "plasticizers" include, but are not limited to, triethyl citrate, tributyl citrate, triacetin, phthalates, polyethylene glycol 6000, and propylene glycol;
non-limiting examples of "barrier ingredients" include, but are not limited to, hypromellose, microcrystalline cellulose, and lactose monohydrate;
non-limiting examples of "stabilizers" include, but are not limited to, magnesium oxide, magnesium carbonate, sodium bicarbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, and ammonia;
"Wet granulation" is a process in which a binder is added to a pharmaceutical powder and the powder is agglomerated together by the bridging or binding action of the binder to produce granules;
the dry granulation is a method of uniformly mixing the powder of the medicine and the auxiliary materials, compressing the mixture into large tablets or blocks, and crushing the large tablets or blocks into particles with required sizes;
the 'fluidized bed granulation' is a method for completing 3 steps of mixing, granulating and drying of the conventional wet granulation in a closed container at one time;
Detailed Description
The raw material sources are as follows:
the following examples may be helpful in understanding the present invention, but the summary of the invention includes, but is not limited to, the following examples.
Example 1 naproxen esomeprazole magnesium multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing naproxen and croscarmellose sodium ND-2HS according to the prescription amount, preparing soft materials by using 10% of povidone K30, granulating by a 20-mesh sieve, drying, adding magnesium stearate according to the prescription amount, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving talcum powder and triethyl citrate with the prescription amount in water, adding 30 percent by mass of Eudragit L30D-55 aqueous dispersion, and uniformly stirring to obtain enteric coating liquid; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain an isolation layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving esomeprazole magnesium and sodium hydroxide according to the prescription amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
Example 2 naproxen esomeprazole magnesium multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing naproxen and croscarmellose sodium ND-2HS according to the prescription amount, preparing soft materials by using 10% of povidone K30, granulating by a 20-mesh sieve, drying, adding magnesium stearate according to the prescription amount, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving talcum powder and triethyl citrate with the prescription amount in water, adding 30 percent by mass of Eudragit L30D-55 aqueous dispersion, and uniformly stirring to obtain enteric coating liquid; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain an isolation layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving esomeprazole magnesium and sodium hydroxide according to the prescription amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
EXAMPLE 3 naproxen esomeprazole magnesium multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing naproxen and croscarmellose sodium ND-2HS according to the prescription amount, preparing soft materials by using 10% of povidone K30, granulating by a 20-mesh sieve, drying, adding magnesium stearate according to the prescription amount, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving talcum powder and triethyl citrate with the prescription amount in water, adding 30 percent by mass of Eudragit L30D-55 aqueous dispersion, and uniformly stirring to obtain enteric coating liquid; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain an isolation layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving esomeprazole magnesium and sodium hydroxide according to the prescription amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
Example 4 naproxen esomeprazole magnesium multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing naproxen and croscarmellose sodium ND-2HS according to the prescription amount, preparing soft materials by using 10% of povidone K30, granulating by a 20-mesh sieve, drying, adding magnesium stearate according to the prescription amount, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving talcum powder and triethyl citrate with the prescription amount in water, adding 30 percent by mass of Eudragit L30D-55 aqueous dispersion, and uniformly stirring to obtain enteric coating liquid; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain an isolation layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving esomeprazole magnesium and sodium hydroxide according to the prescription amount in ethanol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
COMPARATIVE EXAMPLE 1 naproxen Esomeprazole magnesium multilayer tablet (1000 tablets)
TABLE 1 naproxen esomeprazole magnesium multilayer tablet formulation with different barrier layer weight gains
TABLE 2 naproxen esomeprazole magnesium multilayer tablet formulation weighted by different drug containing layers
Remarking: equidz L30D-55 was calculated based on the weight of the polymer, esomeprazole magnesium was calculated based on the weight of esomeprazole, the amount of solvent was not calculated in the weight of the tablet, and comparative examples 1-1, 1-2, 1-3, 1-4 were prepared in the same manner as example 1.
EXAMPLE 5 Nabumetone rabeprazole multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing prescribed amount of nabumetone and crospovidone CL, preparing soft material by using 10% of hydroxypropyl cellulose E5, granulating and drying by a 20-mesh sieve, adding prescribed amount of superfine silica gel powder, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving prescribed amount of talcum powder and polyethylene glycol 6000 in water, adding Eudragit L100-55, and stirring to obtain enteric coating solution; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in absolute ethyl alcohol, sequentially adding microcrystalline cellulose, water and talcum powder, and uniformly stirring to obtain an isolating layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving rabeprazole and potassium hydroxide in a formula amount in absolute ethyl alcohol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
EXAMPLE 6 Nabumetone rabeprazole multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing prescribed amount of nabumetone and crospovidone CL, preparing soft material by using 10% of hydroxypropyl cellulose E5, granulating and drying by a 20-mesh sieve, adding prescribed amount of superfine silica gel powder, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving prescribed amount of talcum powder and polyethylene glycol 6000 in water, adding Eudragit L100-55, and stirring to obtain enteric coating solution; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in absolute ethyl alcohol, sequentially adding microcrystalline cellulose, water and talcum powder, and uniformly stirring to obtain an isolating layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving rabeprazole and potassium hydroxide in a formula amount in absolute ethyl alcohol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
EXAMPLE 7 Nabumetone rabeprazole multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing prescribed amount of nabumetone and crospovidone CL, preparing soft material by using 10% of hydroxypropyl cellulose E5, granulating and drying by a 20-mesh sieve, adding prescribed amount of superfine silica gel powder, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving prescribed amount of talcum powder and polyethylene glycol 6000 in water, adding Eudragit L100-55, and stirring to obtain enteric coating solution; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in absolute ethyl alcohol, sequentially adding microcrystalline cellulose, water and talcum powder, and uniformly stirring to obtain an isolating layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving rabeprazole and potassium hydroxide in a formula amount in absolute ethyl alcohol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
EXAMPLE 8 Nabumetone rabeprazole multilayer tablet (1000 tablets)
The preparation method comprises the following steps:
tablet core: weighing prescribed amount of nabumetone and crospovidone CL, preparing soft material by using 10% of hydroxypropyl cellulose E5, granulating and drying by a 20-mesh sieve, adding prescribed amount of superfine silica gel powder, mixing, and tabletting to obtain a tablet core;
enteric layer: dissolving prescribed amount of talcum powder and polyethylene glycol 6000 in water, adding Eudragit L100-55, and stirring to obtain enteric coating solution; adding the tablet core into a coating pan, starting a machine, and coating an enteric coating layer;
isolation layer: dissolving triethyl citrate in the formula amount in absolute ethyl alcohol, sequentially adding microcrystalline cellulose, water and talcum powder, and uniformly stirring to obtain an isolating layer coating solution; placing the tablet core coated with the enteric layer in a coating pan, starting a machine, and coating the isolating layer;
a medicine-containing layer: dissolving rabeprazole and potassium hydroxide in a formula amount in absolute ethyl alcohol, sequentially adding hydroxypropyl methylcellulose E5, water and talcum powder, and uniformly stirring to obtain a drug-containing layer coating solution; the tablet core coated with the barrier layer is placed in a coating pan and the machine is started to contain the drug layer.
COMPARATIVE EXAMPLE 2 multilayer tablet (1000 tablets) of nabumetone and rabeprazole
TABLE 3 multilayer tablet formulation of nabumetone rabeprazole with different weight gains on the isolating layer
TABLE 4 multilayer tablet formulation of nabumetone rabeprazole with different drug-containing layers weighted
Remarking: the solvent amounts were not calculated in the weight of the tablets, and comparative examples 2-1, 2-2, 2-3, 2-4 were prepared in the same manner as in example 5.
EXAMPLE 9 content uniformity determination
Because the weight of the non-steroidal anti-inflammatory drug in the tablet is twenty-five times that of the proton pump inhibitor, the content of the proton pump inhibitor is low, and the tablet is not easy to mix uniformly, the content uniformity of the tablet can be evaluated by measuring the content of the proton pump inhibitor.
The determination method comprises the following steps: according to appendix XE of the second part of the version 2010 of Chinese pharmacopoeia, 10 test samples are taken and respectively measured, each test sample is placed in a 100mL measuring flask, an appropriate amount of mobile phase is added to completely disintegrate the test samples, the test samples are diluted to scales by the mobile phase, shaken for 30 minutes, filtered, secondary filtrate is taken, the content of esoiprazole magnesium or rabeprazole is measured by high performance liquid phase, the relative content X of the esomeprazole magnesium or rabeprazole with the labeled amount of 100 is respectively calculated, and the average value is calculated
Standard deviation S and relative evaluation deviation A values
When A +1.8S is less than or equal to 15.0, the content uniformity meets the specification.
TABLE 5 determination of the content uniformity of esomeprazole magnesium in examples 1-4 and comparative examples 1-4
| Numbering | Weight gain of drug-containing layer | Content uniformity A +1.8S |
| Example 1 | 7％ | 14.15 |
| Example 2 | 9％ | 12.87 |
| Example 3 | 20％ | 6.29 |
| Example 4 | 25％ | 4.62 |
| Comparative examples 1 to 1 | 7％ | 14.08 |
| Comparative examples 1 to 2 | 7％ | 14.22 |
| Comparative examples 1 to 3 | 4％ | 17.98 |
| Comparative examples 1 to 4 | 5％ | 16.52 |
TABLE 6 determination of content uniformity of rabeprazole in examples 5-8 and comparative examples 2-1-2-4
As can be seen from tables 5-6, when the weight of the drug-containing layer is increased by 7% -25%, the content A +1.8S of esomeprazole magnesium or rabeprazole is less than 15, which accords with the pharmacopoeia regulation; when the weight of the medicine-containing layer is increased by less than 7%, the A +1.8S is more than 15, and the uniformity is unqualified in comparative examples 1-3, 1-4, 2-3 and 2-4.
The reason for the analysis is as follows: because the amount of the main drugs (esomeprazole and magnesium rabeprazole) is fixed, the weight of the drug-containing layer is smaller, the proportion of the main drugs in the formula of the coating solution is larger, the required coating time is shorter, and the coating layer is thinner, so that the content of the tablet is uneven; on the contrary, when the weight of the medicine-containing layer is increased, the proportion of the main medicine in the coating liquid formula is reduced, the longer the required coating time is, the thicker the coating layer thickness is, the better the control of the weight of the medicine-containing layer and the content uniformity of the main medicine is, but if the weight of the medicine-containing layer is increased too much, the cost of the auxiliary materials is increased. Therefore, the weight gain of the drug-containing layer is selected to be in the range of 7-25% from the viewpoint of content uniformity and cost.
And (4) conclusion: the tablet obtained by adding weight of the drug-containing layer within 7% -25% has better content uniformity.
Example 10 stability study
The tablets obtained by the processes of examples 1 to 8, comparative examples 1 to 1, comparative examples 1 to 2, comparative examples 2 to 1 and comparative examples 2 to 2 were subjected to accelerated examination in a constant temperature and humidity chamber at 40. + -. 2 ℃ and a relative humidity of 75. + -. 5% for 6 months, and the results are shown in tables 7 to 8.
TABLE 7 naproxen esomeprazole magnesium multilayer tablet stability study
TABLE 8 stability study of nabumetone rabeprazole multilayer tablets
As can be seen from tables 7 to 8, the tablets obtained in examples 1 to 8 have good stability in an accelerated test for 6 months, and have no obvious change in appearance, related substances and content, while comparative examples 1 to 1, 1 to 2, 2 to 1 and 2 to 2 have dark appearance, obviously increased related substances, reduced content and unstable tablets. The reason for the analysis is as follows: the proton pump inhibitor is sensitive to acid, and the enteric layer is a slightly acidic material, so the weight gain of the isolating layer plays a key role in the stability of the enteric layer. The weight of the isolating layer is increased by less than 5 percent in comparative examples 1-1, 1-2, 2-1 and 2-2, the isolating effect is not ideal, so that esomeprazole or rabeprazole in the drug-containing layer is deteriorated when encountering acid, related substances are increased, and the content is reduced; in examples 1-8, the weight increase of the isolating layer is within the range of 5% -12%, so that a good isolating effect can be achieved, and the obtained tablet is good in stability.
And (4) conclusion: the weight of the isolating layer is increased by 5% -12% in examples 1-8, and the obtained tablet has good stability.
Claims (6)
1. A composition containing a non-steroidal anti-inflammatory drug and a proton pump inhibitor is a multilayer tablet and sequentially comprises a tablet core, an enteric layer, an isolation layer and a drug-containing layer from inside to outside, wherein the tablet core contains the non-steroidal anti-inflammatory drug, and the drug-containing layer contains the proton pump inhibitor, and the composition is characterized in that: the weight of the medicine-containing layer is increased by 7 to 30 percent; the weight of the isolating layer is increased by 5 to 12 percent;
the tablet core comprises a non-steroidal drug, a disintegrating agent, a bonding agent and a lubricating agent;
the enteric layer comprises a casing material, an anti-sticking agent and a plasticizer;
the isolation layer comprises an isolation component, an anti-adhesion agent and a plasticizer;
the drug-containing layer comprises a proton pump inhibitor, a binder, an anti-adhesive agent and a stabilizing agent;
the non-steroidal anti-inflammatory drug is selected from naproxen or nabumetone, and the proton pump inhibitor is selected from esomeprazole magnesium or rabeprazole.
2. The composition of claim 1, wherein the formulation per unit specification is as follows:
tablet core
500mg of non-steroidal anti-inflammatory drug
Disintegrating agent 20-30mg
20-30mg of adhesive
Lubricant 5-10mg
Enteric layer
Casing material 35-40mg
8-14mg of antiadhesive agent
2.5-5mg of a plasticizer,
insulating layer
Isolating component 20-60mg
2-10mg of antiadhesive agent
2-6mg of plasticizer, 5-12% of weight increment of isolating layer,
medicine containing layer
Proton pump inhibitor 20mg
2-90mg of adhesive
1-60mg of antiadhesive agent
1-4mg of stabilizer, and 7-25% of weight of the medicine-containing layer.
3. The composition of claim 1, wherein:
the disintegrant is selected from croscarmellose sodium, crospovidone or sodium carboxymethyl starch;
the adhesive is selected from one or more of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose or sodium carboxymethyl cellulose;
the lubricant is selected from magnesium stearate, aerosil, talcum powder or polyethylene glycol;
the sausage casing material is selected from Ewing, cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate;
the anti-adhesion agent is selected from talcum powder, magnesium stearate or superfine silica powder;
the plasticizer is selected from triethyl citrate, tributyl citrate, triacetin, phthalate, polyethylene glycol 6000 or propylene glycol;
the isolating component is selected from one or more of hydroxypropyl methylcellulose, microcrystalline cellulose or lactose monohydrate;
the stabilizer is selected from magnesium oxide, magnesium carbonate, sodium bicarbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide or ammonia water.
4. The composition of claim 3, wherein:
the disintegrant is selected from croscarmellose sodium ND-2HS, crospovidone CL or crospovidone XL-10;
the adhesive is selected from povidone K30, hydroxypropyl methylcellulose E5 or hydroxypropyl cellulose SL;
the lubricant is selected from magnesium stearate or aerosil;
the Eudragit is selected from Eudragit L30D-55, Eudragit S100 or Eudragit L100;
the anti-adhesion agent is selected from talcum powder, magnesium stearate or superfine silica powder;
the plasticizer is selected from triethyl citrate, tributyl citrate, polyethylene glycol 6000 or propylene glycol;
the isolating component is selected from hydroxypropyl methylcellulose E5 or microcrystalline cellulose;
the stabilizer is selected from magnesium oxide, sodium carbonate, sodium hydroxide or potassium hydroxide.
5. Process for the preparation of a composition according to any one of claims 1 to 4, characterized by comprising the following steps:
(1) tablet core: weighing the non-steroidal drugs and the disintegrating agents according to the prescription amount, preparing soft materials by using adhesives, granulating by 20 meshes, drying, adding the lubricants according to the prescription amount, mixing and tabletting to obtain tablet cores;
(2) enteric layer: dissolving an anti-sticking agent and a plasticizer in water, adding a casing material, and uniformly stirring to obtain an enteric coating solution; adding the tablet core in the step (1) into a coating pan, starting a machine, and coating an enteric coating;
(3) isolation layer: dissolving a plasticizer in ethanol, sequentially adding an isolation component, water and an anti-sticking agent, and uniformly stirring to obtain an isolation layer coating solution; putting the tablet core coated with the enteric-coated layer in the coating pan, starting a machine, and coating an isolating layer;
(4) a medicine-containing layer: dissolving a proton pump inhibitor drug and a stabilizer in ethanol, sequentially adding an adhesive, water and an anti-sticking agent, and uniformly stirring to obtain a drug-containing layer coating solution; placing the tablet core coated with the isolating layer in the coating pan, and starting the machine to contain the medicine layer.
6. Use of a composition according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of gastrointestinal side effects associated with diseases with non-steroidal anti-inflammatory drugs.
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| CN202288921U (en) * | 2011-08-02 | 2012-07-04 | 天津市嵩锐医药科技有限公司 | Compound naproxen esomeprazole tablet |
| CN103479653A (en) * | 2013-10-09 | 2014-01-01 | 山东大学 | Aspirin-esomeprazole compound enteric coated pellet preparation and preparation method |
| CN104208039A (en) * | 2014-08-26 | 2014-12-17 | 杭州新诺华医药有限公司 | Naproxen esomeprazole enteric preparation and preparation method thereof |
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| CN202288921U (en) * | 2011-08-02 | 2012-07-04 | 天津市嵩锐医药科技有限公司 | Compound naproxen esomeprazole tablet |
| CN103479653A (en) * | 2013-10-09 | 2014-01-01 | 山东大学 | Aspirin-esomeprazole compound enteric coated pellet preparation and preparation method |
| CN104208039A (en) * | 2014-08-26 | 2014-12-17 | 杭州新诺华医药有限公司 | Naproxen esomeprazole enteric preparation and preparation method thereof |
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| 埃索美拉唑镁肠溶微丸的制备及其工艺评价;赵玉娜等;《药学与临床研究》;20120228;第20卷(第1期);第40-42、70页 * |
| 复方萘普生钠肠溶-埃索美拉唑镁速释微丸型胶囊剂的研制;沙露平等;《中国药剂学杂志》;20150131;第13卷(第1期);第1-12页 * |
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